Neurovascular–immune mediator dynamics in migraine: State-dependent effects of caffeine

Migraine is a complex neurovascular disorder involving interactions between trigeminovascular, endothelial, and neuroimmune pathways. Dysregulation of key mediators—calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)—is central to its pathophysiology. However, their phase-dependent dynamics and acute responsiveness to caffeine remain unclear. This study evaluated phase-specific alterations in these mediators and their intra-individual response to caffeine.

A total of 327 participants (174 migraine patients and 153 healthy controls) were included. Migraine patients were assessed across interictal and ictal phases using a within-subject design. During ictal attacks, participants underwent a randomized, double-blind, placebo-controlled crossover intervention with 200 mg caffeine or placebo. Blood samples were collected at baseline (T0) and 60 min post-intervention (T1). Mediators were measured using ELISA and analyzed with linear mixed-effects models.

CGRP, NO, IL-6, and TNF-α were significantly elevated during migraine, particularly in the ictal phase, while endothelin-1 was reduced. Caffeine significantly decreased CGRP and NO levels and increased endothelin-1 compared with placebo. IL-6 and TNF-α showed modest reductions. Responses varied between individuals, with greater effects observed in those with higher baseline levels.

Migraine is characterized by dynamic, phase-dependent neurovascular and inflammatory alterations. Acute caffeine administration modulates key mediators, promoting a shift toward a more vasoconstrictive vascular balance and reduced trigeminovascular activation. These effects are influenced by baseline mediator levels, highlighting the importance of state-dependent responsiveness. The findings emphasize the need for temporally sensitive and individualized approaches in understanding migraine pathophysiology and therapeutic modulation.